Leveraging high-throughput proteomics and AI-based protein folding to accelerate VAV1 molecular glue discovery.
13 affiliations
- 1The Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas, USA. [email protected].
- 2Center for NextGen Therapeutics, Baylor College of Medicine, Houston, Texas, USA. [email protected].
- 3Graduate School of Biomedical Sciences, Baylor College of Medicine, Houston, Texas, USA. [email protected].
- 4The Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas, USA.
- 5Center for NextGen Therapeutics, Baylor College of Medicine, Houston, Texas, USA.
- 6Graduate School of Biomedical Sciences, Baylor College of Medicine, Houston, Texas, USA.
- 7Thermo Fisher Scientific, San Jose, California, USA.
- 8YDS Pharmatech, Inc., Albany, New York, USA.
- 9SandboxAQ, Palo Alto, California, USA.
- 10Receptor.AI Inc., 223 Concord Turnpike, Cambridge, Massachusetts, USA.
- 11The Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas, USA. [email protected].
- 12Center for NextGen Therapeutics, Baylor College of Medicine, Houston, Texas, USA. [email protected].
- 13Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA. [email protected].
Abstract
This study reports a series of CRBN molecular glues that selectively induce proteasomal degradation of VAV1, a hematopoietic-specific signaling protein and key target in hematological malignancies and autoimmune diseases. Using unbiased global proteomics, we identify phenyl-glutarimide derivatives (e.g., NGT-201-12) as effective VAV1 degraders that engage its C-terminal SH3 domain (SH3-2). We elucidate a non-canonical RT-loop degron (RDxS motif, residues 796-799) in SH3-2, distinct from previously characterized G-loop degrons, supported by the physics- and AI-driven GluePlex workflow and site-directed mutagenesis. Applying Free Energy Perturbation (FEP) to predicted ternary structures yields cooperativity metrics that correlate with degradation potency, overcoming limitations of standard docking and enabling prospective ranking of analogs-even from weak initial binders. We further show that conformational restriction via halogen substitution (e.g., NGT-201-18) potentiates degradation, a principle rationalized by DFT calculations, while comprehensive SAR studies chart a roadmap for next-generation degraders. Dose-response proteomics confirms VAV1 as the primary target and reveals LIMD1, bearing a canonical G-loop, as an off-target, showing that one glue can engage disparate degrons. These findings expand the landscape of CRBN neosubstrate recognition and offer a therapeutic strategy for targeting VAV1.
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BibTeX
@article{lin2026leveraging,
title = {{Leveraging high-throughput proteomics and AI-based protein folding to accelerate VAV1 molecular glue discovery.}},
author = {Hanfeng Lin and Xin Yu and Haiyang Zheng and Ran Cheng and Min Zhang and Xiaoli Qi and Yen-Yu Yang and Shengmin Zhou and Rui Qi and Ly Le and Andrea Bortolato and Semen Yesylevskyy and Alan Nafiiev and Xing Che and Jin Wang},
journal = {Nature communications},
year = {2026},
month = sep,
doi = {10.1038/s41467-026-77657-z},
url = {https://europepmc.org/article/MED/42869914},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Leveraging high-throughput proteomics and AI-based protein folding to accelerate VAV1 molecular glue discovery.
AU - Hanfeng Lin
AU - Xin Yu
AU - Haiyang Zheng
AU - Ran Cheng
AU - Min Zhang
AU - Xiaoli Qi
AU - Yen-Yu Yang
AU - Shengmin Zhou
AU - Rui Qi
AU - Ly Le
AU - Andrea Bortolato
AU - Semen Yesylevskyy
AU - Alan Nafiiev
AU - Xing Che
AU - Jin Wang
PY - 2026
DA - 2026/09/12
JO - Nature communications
DO - 10.1038/s41467-026-77657-z
UR - https://europepmc.org/article/MED/42869914
AB - This study reports a series of CRBN molecular glues that selectively induce proteasomal degradation of VAV1, a hematopoietic-specific signaling protein and key target in hematological malignancies and autoimmune diseases. Using unbiased global proteomics, we identify phenyl-glutarimide derivatives (e.g., NGT-201-12) as effective VAV1 degraders that engage its C-terminal SH3 domain (SH3-2). We elucidate a non-canonical RT-loop degron (RDxS motif, residues 796-799) in SH3-2, distinct from previously characterized G-loop degrons, supported by the physics- and AI-driven GluePlex workflow and site-directed mutagenesis. Applying Free Energy Perturbation (FEP) to predicted ternary structures yields cooperativity metrics that correlate with degradation potency, overcoming limitations of standard docking and enabling prospective ranking of analogs-even from weak initial binders. We further show that conformational restriction via halogen substitution (e.g., NGT-201-18) potentiates degradation, a principle rationalized by DFT calculations, while comprehensive SAR studies chart a roadmap for next-generation degraders. Dose-response proteomics confirms VAV1 as the primary target and reveals LIMD1, bearing a canonical G-loop, as an off-target, showing that one glue can engage disparate degrons. These findings expand the landscape of CRBN neosubstrate recognition and offer a therapeutic strategy for targeting VAV1.
SN - 2041-1723
ER -